Crohn's disease represents one of the inflammatory bowel diseases, and it affects 1.4 million Americans. Crohn's disease causes breaks in the lining of the small and large intestines and can affect the entire digestive system. Ulcerative colitis is usually restricted to the large intestine and involves inflammation of more superficial layers of the bowel lining, while Crohn's also affects deeper layers. The disease likely increases the risk of cancer in the area of inflammation. For example, individuals with Crohn's disease involving the small bowel are at higher risk for small intestinal cancer. Similarly, people with Crohn's colitis have a relative risk of 5.6 for developing colon cancer. In addition to intestinal problems—cramps, diarrhea and rectal bleeding—Crohn's can also cause painful skin ulcers, eye conditions that can interfere with vision, inflammation of the liver and arthritis, among other complications. Symptoms usually begin in adolescence or young adulthood and then intermittently flare up.
There are treatments for Crohn's, but no cure. Anti-inflammatory drugs, immune system suppressants, antibiotics and surgery are all used, with varying degrees of success. Most treatments have side effects that can range from trivial to debilitating.
The etiology of Crohn's diseases is complex and multi-factorial. It has a strong genetic link; for example, the disease runs in families and those with a sibling with the disease are 30 times more likely to develop it than the normal population. Ethnic background may be a risk factor. Mutations in the CARD15 gene (also known as the NOD2 gene) have been suggested to associate with Crohn's disease. The frequency of variations in the gene for a receptor of a cytokine (interleukin-23, or IL-23) was significantly different in people with Crohn's disease as compared to that with healthy people. Therapy targeting p40, a subunit of IL-23, can inhibit the activity of IL-23 in Crohn's disease (Mannon P, N. Engl. J. Med. 351:2069, 2004). Screening for colon cancer with colonoscopy is recommended for anyone who has had Crohn's colitis for at least eight years.
Interleukin-23 is a newly identified cytokine and it belongs to the IL-6 superfamily. IL-23 is composed of a common p40 subunit (shared with IL-12) and an IL-23 specific p19 subunit. The IL-23 receptor is a heterodimeric complex that consists of the common IL-12Rβ1 chain and a unique IL-23Rα chain, which is the main signaling chain of the receptor [Parham et al. 2002].
Abnormalities in the immune system and secretion of various cytokines have also been invoked as being causes of Crohn's disease. Crohn's disease is thought to be an autoimmune disease, with inflammation stimulated by an over-active Th17 cytokine response. An increasing body of evidence also exists in favor of the hypothesis that Crohn's disease may results from an impaired innate immunity, which may be due to (at least in part) to impaired cytokine secretion by macrophages.
The human IL-23R gene is composed of at least 12 exons flanking a 92.5 kb genomic region within chromosome 1p32.1-p31.2. The mRNA of IL-23R is 2.8 kb long and comprises 11 exons (NM—144701). The transcribed mRNA is translated into a protein of 629 amino acids, resulting in a type-I transmembrane protein which contains a signal peptide, an N-terminal fibronectin III-like domain and a 252 residue cytoplasmic domain with three potential tyrosine phosphorylation sites [Parham et al. 2002]. IL-23R is a member of the hemopoietin receptor superfamily. The IL-23 receptor complex can be selectively expressed on the “Th17” subset of CD4+ T lymphocytes and low levels of IL-23R expression have also been detected on monocytes, macrophages and dendritic cells [Parham et al, 2002]. The function of IL-23 has not been clearly defined, although it has been reported to work in tandem with interleukin-6 (IL-6) and interleukin-21 (IL-21) to drive the proliferation and functional development of CD4+ Th17 cells. Binding of IL-23 to its receptor activates STAT3 and IL-17 production is subsequently induced.
There are structural and functional similarities between IL-23/IL-23R and IL-12/IL-12R signaling, both may have possible related regulatory functions in T cell development, and T cell-mediated immune responses which bridge innate and adaptive immunity. IL-12/IL-12R signaling plays a pivotal role in Th1 cell responses by promoting IFN-γ production during infection; and IL-23/IL-23R signaling is the central molecule of the Th17 cell differentiation by up-regulation IL-17 production in inflammatory and auto-immune responses. The importance of IL-23R in controlling innate immunity via Th17 cells may underscore why the IL-23R gene also has been demonstrated to confer susceptibility to several autoimmune diseases, including psoriasis [Capon et al. 2007; Nair et al. 2008], ankylosing spondylitis [Rueda et al. 2008], multiple sclerosis [Illes et al. 2008; Roos et al. 2007; Begovich et al. 2007] and inflammatory bowel diseases (both Crohn's Disease and/or ulcerative colitis) [Duerr et al. 2006; Raelson et al. 2007]. In addition, a separate study by the Wellcome Trust Case Control Consortium and the Australo-Anglo-American Spondylitis Consortium [2007] found evidence to suggest that IL-23R may be a common susceptibility factor for the major ‘sero-negative’ diseases.
Zhang et al. have reported a number of IL-23R splice variants for IL-23R mRNA and some variants are reported in cancer cells. No information exists, however, if any splice variant(s) may be associated with inflammatory diseases, let alone inflammatory bowel diseases such as Crohn's disease.
A recent genome wide association (GWA) study first demonstrated that variants of IL-23R is one of the genetic factors contributing to Crohn's disease. Among the SNPs within IL-23R, one (rs11209026, R381Q) is negatively associated with Crohn's disease, which implies that the Q allele may play a protective role in the pathogenesis of Crohn's diseases [Duerr et al. 2007]. Afterwards, more GWA studies support this R/Q SNP to other diseases from different populations [Jacobs et al, 2007].
There is a continuing need to identify novel IL-23R polymorphic elements and novel markers for predicting inflammatory bowel diseases in humans.